1. Technical Field
This invention relates to computer assisted methods for identifying target binding sites on a molecule of interest and methods for designing ligands which bind to a molecule of interest.
2. Background Information
Structure-based drug design is a major activity in pharmaceutical laboratories. The recent development of HIV-1 protease inhibitors is a major testimony to that effect. In structure-based drug design, the overall goal is to design a small molecule that binds to a specific site in a target molecule, usually a protein or other macromolecule. Where the target protein is an enzyme, the specific target site is often the substrate binding site or active site of the enzyme. Where the target protein is a receptor, the specific target site is often the binding site for a natural ligand of the receptor. In all cases the goal is to alter the behavior of the target molecule in a predetermined way as a result of the binding of the small molecule.
The starting point in the design process is the availability of the high resolution structure of the target protein. As noted above, in most situations, the target site for binding of the small molecule drug is the substrate binding or active site of an enzyme or the ligand binding site of a receptor. In some cases the location of these sites on the surface of the target protein is known from biochemical or structural studies. For this reason, most lead compounds are analogues of natural ligands or substrates. The situation is more complicated if the location of these sites is not known or if targeting a second binding site is required (a situation necessary, e.g., in cases where resistance towards an existing drug develops). Furthermore, the optimization of lead compounds is a very demanding endeavor requiring the chemical synthesis and characterization of a very large number of derivatives. It is evident that the availability of an algorithm that can identify, map, and rank binding sites and design ligands would have a positive impact in drug design. The present invention provides such capabilities.